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Selective Antagonism of 5-Reduced Neurosteroid Effects at GABA_A Receptors

Departments of Psychiatry (S.M., Y.H., M.W., A.S., A.B., C.F.Z.), Molecular Biology and Pharmacology (X.J., A.S.E., D.F.C.), Anatomy and Neurobiology (S.M., C.F.Z.), and Anesthesiology (B.D.M., A.S.E.), Washington University School of Medicine, St. Louis, Missouri

Although neurosteroids have rapid effects on GABA_A receptors, study of steroid actions at GABA receptors has been hampered by a lack of pharmacological antagonists. In this study, we report the synthesis and characterization of a steroid analog, (3,5)-17-phenylandrost-16-en-3-ol (17PA), that selectively antagonized neurosteroid potentiation of GABA responses. We examined 17PA using the 122 subunit combination expressed in Xenopus laevis oocytes. 17PA had little or no effect on baseline GABA responses but antagonized both the response augmentation and the direct gating of GABA receptors by 5-reduced potentiating steroids. The effect was selective for 5-reduced potentiating steroids; 5-reduced potentiators were only weakly affected. Likewise, 17PA did not affect barbiturate and benzodiazepine potentiation. 17PA acted primarily by shifting the concentration response for steroid potentiation to the right, suggesting the possibility of a competitive component to the antagonism. 17PA also antagonized 5-reduced steroid potentiation and gating in hippocampal neurons and inhibited anesthetic actions in X. laevis tadpoles. Analogous to benzodiazepine site antagonists, the development of neurosteroid antagonists may help clarify the role of GABA-potentiating neurosteroids in health and disease.

Address correspondence to: Dr. Steven Mennerick, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8134, St. Louis, MO 63110. E-mail: menneris{at}psychiatry.wustl.edu

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